Pencilbeam Irradiation Technique for Whole Brain Radiotherapy: Technical and Biological Challenges in a Small Animal Model

Abstract

We have conducted the first in-vivo experiments in pencilbeam irradiation, a new synchrotron radiation technique based on the principle of microbeam irradiation, a concept of spatially fractionated high-dose irradiation. In an animal model of adult C57 BL/6J mice we have determined technical and physiological limitations with the present technical setup of the technique. Fifty-eight animals were distributed in eleven experimental groups, ten groups receiving whole brain radiotherapy with arrays of 50 µm wide beams. We have tested peak doses ranging between 172 Gy and 2,298 Gy at 3 mm depth. Animals in five groups received whole brain radiotherapy with a center-to-center (ctc) distance of 200 µm and a peak-to-valley ratio (PVDR) of ∼ 100, in the other five groups the ctc was 400 µm (PVDR ∼ 400). Motor and memory abilities were assessed during a six months observation period following irradiation. The lower dose limit, determined by the technical equipment, was at 172 Gy. The LD50 was about 1,164 Gy for a ctc of 200 µm and higher than 2,298 Gy for a ctc of 400 µm. Age-dependent loss in motor and memory performance was seen in all groups. Better overall performance (close to that of healthy controls) was seen in the groups irradiated with a ctc of 400 µm.

DNA double strand breaks in the acute phase after synchrotron pencilbeam irradiation

“…We have shown in our experiements that the extent of DNA damage caused by pencilbeam irradiation is dose-dependent, which is in agreement with results reported by Priyadarshika and colleagues for the classsic microbeam radiation approach [10]. The development of pycnotic nuclei in the centres of the beam path corresponds to the results of our earlier experiments, where at 6 months after irradiation the centres of the beam paths were almost devoid of living cells [4]. From the analysis of the H2AX study we understand that the volume in which the DNA damage occurs is not limited to the path of the beam but becomes larger than the beam in a dosedependent fashion.…”

“…Having previously demonstrated the feasibility of pencilbeam irradiation with the technical setup available at the biomedical beamline ID 17 of the ESRF [4], we have now designed a first experiment to study the consequences of pencilbeam irradiation on DNA integrity.…”

Neurocognitive sparing of desktop microbeam irradiation

“…The peak-to-valley dose ratio (PVDR) has been measured 16 at the entrance plane and decreased to 14 at the exit plane, so the equivalent integral dose of 10Gy BB simulated to be ≈ 46Gy in peaks [ 13 ]. But several histological studies after high dose brain MRT have shown a discrete band of neuronal and glial nuclei loss only along the beam path [ 54 – 57 ]. This observation supports the idea that surviving cells in the valley region play the main role in maintaining tissue function and compensating for the loss of functional cells in the peak region.…”

Microbeam radiation therapy — grid therapy and beyond: a clinical perspective

“… 14 , 71 Irradiation with monoplanar beam arrays as well as in pencilbeam technique has caused only minimal functional deficits in the brain at peak doses significantly higher than those currently used in conventional radiotherapy. 60 , 69 , 103 It is hoped to see similar function-preserving effects when using MRT in the lung while maintaining an effective antitumour effect.…”

“… 59 The generation of pencil beams was tested successfully in the hope that this might result in even higher normal tissue tolerance doses. 60 Dose enhancement was looked at in relation to MRT, especially with nanoparticles. 61 , 62 Advice was produced for the optimal energy spectrum to be used in any clinical trials of MRT.…”